# Role of autoreactivity in pathogenesis of chronic graft versus host disease

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2024 · $879,263

## Abstract

Allogeneic hematopoietic cell transplantation (Allo-HCT) is a curative therapy for patients with hematological
malignancies (i.e. leukemia and lymphoma), through graft versus leukemia/lymphoma (GVL) effect mediated
by alloreactive donor T cells. However, graft-versus-host disease (GVHD) caused by the same alloreactive T
cells remains a major obstacle. Chronic GVHD (cGVHD), a systemic autoimmune-like syndrome, remains a
major cause of morbidity and mortality in long-term survivors of Allo-HCT. During the past decade, we have
used murine and humanized murine models of cGVHD and biospecimens from cGVHD patients to
demonstrate that CD4+ T cells and B cells and their interactions in GVHD target tissues such as the liver, lung
and skin play a critical role in the pathogenesis and persistence of the disease. The premise of this new
proposal is that deeper mechanistic understanding of the interactions between non-circulating tissue-
resident CD4+ memory T (Trm) and tissue-resident B (Brm) cells in GVHD target tissues will identify
new therapeutic targets for prevention or treatment of cGVHD. In Aim 1, we will determine whether CD4+
Trm cells initiate formation of tertiary lymphoid structures (TLS) in GVHD target tissues, in which Ly108+ stem
cell-like progenitors maintain the pool of Trm and Brm to perpetuate cGVHD pathogenesis. We will also
develop novel cell-penetrating PS-Cas9-gRNA to target STAT3 in donor T cells to prevent development of
pathogenic CD4+ Trm and cGVHD while preserving GVL activity, because our recent studies indicate that
STAT3 is required for Trm development. In Aim 2, we will determine whether B cell helper PD-1hiPSGL1loCD4+
Trh cells interact with T-bet+ Brm cells to produce autoantibodies that augment systemic tissue damage. In
Aim 3, we will determine whether non-B cell helper PSGL1hiCD4+ Trm cells interact with dendritic cells,
macrophages, and fibroblasts in cGVHD target tissues to mediate damage and fibrosis in an IL-33/ST2
pathway-dependent manner. These studies have high biological and translational significance and may lead to
a paradigm shift in our understanding of cGVHD pathogenesis and to development of novel approaches for
preventing and treating cGVHD.

## Key facts

- **NIH application ID:** 10879392
- **Project number:** 1R01HL170099-01A1
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** Defu Zeng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $879,263
- **Award type:** 1
- **Project period:** 2024-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879392

## Citation

> US National Institutes of Health, RePORTER application 10879392, Role of autoreactivity in pathogenesis of chronic graft versus host disease (1R01HL170099-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10879392. Licensed CC0.

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